Cancers of the human esophagus are the eighth most common malignancy. Worldwide, greater than 90% of esophageal cancers are squamous cell carcinomas (SCCs); a multifactorial disease with a significant behavioral component. A large majority of esophageal SCC patients present with advanced, metastatic disease. Five year survival rate in such cases is less than 10%. Epidemiological studies have identified tobacco use and alcohol consumption as the two main risk factors for esophageal SCC in developed countries. Recent evidence suggests that the risk for esophageal SCC remains high for almost a decade in smokers even after they quit tobacco use. There is a necessity for developing effective strategies that inhibit progression of precancerous lesions to clinical disease in this high risk population of former tobacco smokers. Primary chemoprevention is a viable approach in achieving this important health objective. N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in the Fischer 344 rat is a valuable animal model to identify putative chemopreventive agents against this disease. The multistep process of tumor development in this model closely mimics the progression of human esophageal SCC in former tobacco smokers. Therefore, this animal model is an ideal surrogate to identify agents that can inhibit progression of precancerous lesions to malignant tumors. In this proposal we outline our strategy to identify compounds that inhibit tumor development when given subsequent to carcinogen exposure. These agents will potentially inhibit progression of precancerous lesions to frank tumors and may be valuable for use as chemopreventive agents in former tobacco smokers. During the course of these studies, we will also identify morphological and molecular markers that may help assess the efficacy of these compounds. Studies in Specific Aim 1 will evaluate the effects of a known chemopreventive, freeze-dried strawberries on several known morphological and molecular markers to validate their use in human clinical studies. In Specific Aim 2, we will determine the efficacy of three additional chemopreventive agents against tumor progression. Further studies will be undertaken to develop a combination of agents that may have synergistic activity. In Specific Aim 3 we will identify novel biomarkers for future use in human clinical studies. Overall, the results from this proposal will provide important data to enhance our understanding of the molecular mechanisms of malignant progression of esophageal precancerous lesions and will identify candidate chemoprevention agents to reduce esophageal cancer risk in former tobacco smokers.